1. Field of the Invention
The present invention relates to novel orally bioavailable carbapenem antibiotics having a dithioacetal moiety in the 3-position and non-toxic pharmaceutically acceptable salts thereof. The carbapenems of the instant invention have been found to have antimicrobial activity. Therefore, the present carbapenem antibiotics and pharmaceutical compositions thereof are useful in the treatment of antibacterial infections in humans and other animals, either alone or in combination with other antibiotics.
Also disclosed herein are processes for the preparation of said carbapenem antibiotics and to certain novel intermediates.
2. Nomenclature
The terminology for compounds of this class may either be based upon the root name "carbapenem" which employs a trivial system of nomenclature or on the systematic name according to Chemical Abstracts. In the present application, the positions are numbered according to the Chemical Abstract system, for example, 3-R.sup.3 -4-R.sup.2 -6-R.sup.1 -7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid as shown in the following formula ##STR2## The term "carbapenem", as used herein as a class of compounds, is intended to be used interchangeably with the name 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. However, in all instances, the numbering system employed will be the numbering system according to Chemical Abstracts as illustrated above.
3. Disclosure Statement
A great number of carbapenem antibiotics are known in the art. This class of antibiotics is typefied by thienamycin (U.S. Pat. No. 3,950,357 issued Apr. 13, 1976 to Kahan et al.) which was first isolated from fermentation and exhibits a broad spectrum of antibiotic activity. Imipenem (U.S. Pat. No. 4,194,047 issued Mar. 18, 1980 to Christensen et al.), a chemically more stable derivative of thienamycin, was subsequently developed. ##STR3##
More recent developments include 3-(substituted thio)-4-methylcarbapenems of formula II which is disclosed in Shih et al., Heterocycles, 21, 29-40 (1984). ##STR4##
U.S. Pat. No. 4,683,301 issued on Jul. 28, 1987 to Choung relates, inter alia, to carbapenems of formula III ##STR5## in which and R.sup.10 and R.sup.11 each is substituted or unsubstituted alkyl, cycloalkyl, phenyl or taken together constitute C.sub.5-6 alkylidene.
U.S. Pat. No. 4,880,922, issued on Nov. 14, 1989 to Dextraze, relates to carbapenems of the formula ##STR6## in which R is hydrogen or alkyl, R.sup.6 is C.sub.1-6 alkyl; n is 1 to 3 and ##STR7## represents an aromatic 5- or 6- membered N-containing heterocyclic ring containing 0-3 additional hetero atoms selected from O, S or N, said aromatic ring being optionally substituted at available ring carbon or nitrogen atoms by C.sub.1-4 substituents, and said ring being attached to S through a ring carbon atoms and having a ring nitrogen which is quaternized by the group R.sup.6.
European Patent Applications Nos. 169,410 and 168,707 both published on Jul. 2, 1984 disclose a broad class of carbapenems among which are compounds of the formula ##STR8## in which R is hydrogen or methyl.
Another relevant art of the instant invention can be found in Sato et al., in The Journal of Antibiotics, 40, 4, pp 483-495 (1987) in which carbapenems of the following structures are disclosed ##STR9##
Despite general improvements in stability and spectrum of antibiotic activity of carbapenems since imipenem and thienamycin, there is still no reports of carbapenems having any significant oral bioavailability and oral activity. To our great surprise, certain dithioacetal and dithioketal carbapenems of the invention have shown significant oral bioavailability and oral antibiotic activity. Thus, it is the object of the present application to provide a novel class of carbapenms which have been discovered to have the unexpected properties in addition to potent in vitro antimicrobial activity. Thus, the compounds of the present invention are greatly useful in the treatment of infectious diseases in humans and other animals.